The standard treatment for locally advanced rectal cancer involves chemotherapy and radiation, known as 5FUCMT, (the chemotherapy drugs 5-fluorouracil/capecitabine and radiation therapy) prior to surgery. Although radiation therapy to the pelvis has been a standard and important part of treatment for rectal cancer and has been shown to decrease the risk of the cancer coming back in the same area in the pelvis, some patients experience undesirable side effects from the radiation and there have been important advances in chemotherapy, surgery, and radiation which may be of benefit. The purpose of this study is to compare the effects, both good and bad, of the standard treatment of chemotherapy and radiation to chemotherapy using a combination regimen known as FOLFOX, (the drugs 5-fluorouracil (5-FU), oxaliplatin and leucovorin) and selective use of the standard treatment, depending on response to the FOLFOX. The drugs in the FOLFOX regimen are all FDA (Food and Drug Administration) approved and have been used routinely to treat patients with advanced colorectal cancer.

Patients will receive FOLFOX chemotherapy once every two weeks for 6 cycles total over a period of 12 weeks. After completing FOLFOX chemotherapy, the patient will have an MRI scan or endorectal ultrasound (ERUS) to examine the tumor. If the tumor has not decreased in size by at least 20%, the patient will receive 5FUCMT (radiation with chemotherapy). If the tumor has decreased in size by 20%, then the patient will proceed directly to surgery.

If all borders of the tumor are normal post surgery, then the patient receives six additional cycles of FOLFOX chemotherapy. If all borders of the tumor are not normal then the patient receives chemoradiation therapy for 5.5 weeks after surgery. After chemoradiation, additional cycles of FOLFOX or similar chemotherapy will be recommended for 4 cycles or 8 weeks. Patient observation with follow up evaluations and event monitoring will occur up to 8 years post randomization.

Drug: FOLFOX (chemotherapy)

Oxaliplatin 85 mg/m^2 IV over 2 hours on day 1, leucovorin 400 mg/m^2 bolus IV over 2 hours on day 1 and 5-fluorouracil 400 mg/m^2 bolus over 5-15 minutes then 2400 mg/m^2 continual over 46-48 hours total dose IV on days 1-2. The treatment schedule repeats based on the group. Dose modifications are allowed based on adverse events.

Other: 5 FUCMT (chemoradiation)

5-fluorouracil 225 mg/m^2 per day continuous IV infusion administered concurrently with radiation therapy for 5 or 7 days per week OR capecitabine 825 mg/m^2 twice daily administered orally and concurrently with radiation therapy for 5 days per week. Dose modifications are allowed based on adverse events.

Procedure: surgery

low anterior resection with total mesorectal excision

Procedure: magnetic resonance imaging or endorectal ultrasound

Active Comparator: Group 2

Patients receive 5FUCMT including chemotherapy and radiation therapy for 5.5 weeks. Patients will be given either 5-fluorouracil or capecitabine and radiation therapy. After the chemoradiation therapy is completed, patients will proceed directly to surgery. Post-surgery, patients will receive FOLFOX chemotherapy once every two weeks for 8 cycles total over a period of 16 weeks. Patient observation with follow up evaluations and event monitoring will occur up to 8 years post randomization.

Drug: FOLFOX (chemotherapy)

Oxaliplatin 85 mg/m^2 IV over 2 hours on day 1, leucovorin 400 mg/m^2 bolus IV over 2 hours on day 1 and 5-fluorouracil 400 mg/m^2 bolus over 5-15 minutes then 2400 mg/m^2 continual over 46-48 hours total dose IV on days 1-2. The treatment schedule repeats based on the group. Dose modifications are allowed based on adverse events.

Other: 5 FUCMT (chemoradiation)

5-fluorouracil 225 mg/m^2 per day continuous IV infusion administered concurrently with radiation therapy for 5 or 7 days per week OR capecitabine 825 mg/m^2 twice daily administered orally and concurrently with radiation therapy for 5 days per week. Dose modifications are allowed based on adverse events.

Procedure: surgery

low anterior resection with total mesorectal excision

Detailed Description:

OUTLINE: This is a multicenter, phase II/III study. Patients are stratified according to ECOG performance status (0 or 1 vs 2) and randomized to 1 of 2 treatment regimens. Patients will receive full supportive care while on this study.

OBJECTIVES:

Primary

Phase II component: To assure that neoadjuvant FOLFOX followed by selective use of 5FUCMT group (Group 1) maintains the current high rate of pelvic R0 resection and is consistent with non-inferiority for time to local recurrence (TLR).

Phase III component: To compare neoadjuvant FOLFOX followed by selective use of 5FUCMT (Group 1) to standard 5FUCMT (Group 2) with respect to the co-primary endpoints of the Time to Local Recurrence (TLR) and Disease-Free Survival (DFS).

Secondary

To determine if the neoadjuvant FOLFOX followed by selective use of 5FUCMT (Group 1) is non-inferior to the standard group 5FUCMT (Group 2) with respect to the proportion of patients who achieve a pathologic complete response (pCR) at the time of surgical resection.

To determine if the neoadjuvant FOLFOX followed by selective use of 5FUCMT (Group 1) is non-inferior to the standard 5FUCMT (Group 2) with respect to overall survival.

To evaluate and compare the adverse event profile and surgery complications between two groups.

To estimate the proportion of patients in the selective group (Group 1) who receive: 1) pre-operative 5FUCMT; 2) post-operative 5FUCMT; 3) either pre- or post-operative 5FUCMT.

Event monitoring of patients will continue up to 8 years post randomization.

Eligibility

Ages Eligible for Study:

18 Years and older

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Registration Inclusion Criteria:

Age ≥ 18 years at diagnosis

Diagnosis of rectal adenocarcinoma

Radiologically measurable or clinically evaluable disease as defined in the protocol

ECOG Performance Status (PS): 0, 1 or 2

For this patient, the standard treatment recommendation in the absence of a clinical trial would be combined modality neoadjuvant chemoradiation followed by curative intent surgical resection

Candidate for sphincter-sparing surgical resection prior to neoadjuvant therapy according to the primary surgeon

Primary surgeon is credentialed or is willing to be credentialed in Total Mesorectal Excision (TME), which entails submission of photos of a single TME specimen either before enrolling the first patient or by using the surgeon's 1st accrued case.

Clinical Stage: T2N1, T3N0, T3N1.

N2 disease is to be estimated as four or more lymph nodes that are ≥ 10 mm.

Clinical staging should be estimated based on the combination of the following assessments: physical exam by the primary surgeon, CT or PET/CT scan of the chest/abdomen/pelvis and either a pelvic MRI or an ultrasound (ERUS). If a pelvic MRI is peformed, it is acceptable to perform CT of the chest/abdomen, ommitting CT imaging of the pelvis.

The following laboratory values obtained ≤ 28 days prior to registration:

Absolute neutrophil count (ANC) ≥ 1500/mm^3

Platelet count ≥ 100,000/mm^3

Hemoglobin > 8.0 g/dL

Total bilirubin ≤ 1.5 x upper limit of normal (ULN)

SGOT (AST) ≤ 3 x ULN

SGPT (ALT) ≤ 3 x ULN

Creatinine ≤1.5 x ULN

Negative pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only

Patient of child-bearing potential is willing to employ adequate contraception

Provide informed written consent

Willing to return to enrolling medical site for all study assessments

Registration Exclusion Criteria:

Clinical T4 tumors

Primary surgeon indicates need for abdominoperineal (APR) at baseline

Evidence that the tumor is adherent to or invading the mesorectal fascia on imaging studies such that the surgeon would not be able to perform an R0 resection (one with negative margins)

Tumor is causing symptomatic bowel obstruction (patients who have had a temporary diverting ostomy are eligible).

Chemotherapy within 5 years prior to registration. Hormonal therapy is allowable if the disease free interval is ≥ 5 years.

Any prior pelvic radiation

Other invasive malignancy ≤ 5 years prior to registration. Exceptions are colonic polyps, non-melanoma skin cancer or carcinoma in-situ of the cervix.

Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects.

Pregnant women

Nursing women

Men or women of childbearing potential who are unwilling to employ adequate contraception

Co-morbid illnesses or other concurrent disease which, in the judgment of the clinician obtaining informed consent, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.

Contacts and Locations

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01515787